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We instead hypothesized that degeneration of the nigrostriatal dopaminergic system enhances the clinical penetrance of early\u2010stage AD. To determine the effect of striatal dopamine (DA) on the pathological effects in an experimental model of AD, APP<jats:sub>SWE<\/jats:sub>\/PS1\u0394E9 mice received striatal injections of the neurotoxin 6\u2010hydroxydopamine (6OHDA). Animals were tested in a Barnes maze protocol and in a water T\u2010maze protocol at different ages to determine the onset of cognitive impairment. APP<jats:sub>SWE<\/jats:sub>\/PS1\u0394E9 mice that received 6OHDA injections showed significant impairment in Barnes maze performance at an earlier age than controls. Additionally, at 12 months of age, APP<jats:sub>swe<\/jats:sub>\/PS1\u0394E9\u2009+\u20096OHDA mice demonstrated worse behavioral flexibility than other groups in a task\u2010switch phase of the water T\u2010maze. To determine the neuroprotective effects of dopaminergic neurotransmission against amyloid\u2010\u03b2<jats:sub>42<\/jats:sub> (A\u03b2<jats:sub>42<\/jats:sub>) toxicity, neuronal branch order and dendrite length were quantified in primary medium spiny neuron (MSN) cultures pretreated with increasing doses of the D<jats:sub>1<\/jats:sub> and D<jats:sub>2<\/jats:sub> receptor agonists before being exposed to oligomerized A\u03b2<jats:sub>42<\/jats:sub>. Although there were no differences in A\u03b2 peptide levels or plaque burden among the groups, in murine MSN culture dopaminergic agonists prevented a toxic response to A\u03b2<jats:sub>42.<\/jats:sub> Depletion of DA in the striatum exacerbated the cognitive impairment seen in a mouse model of early\u2010stage AD; this may be due to a protective effect of dopaminergic innervation against A\u03b2 striatal neurotoxicity. \u00a9 2015 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/jnr.23592","type":"journal-article","created":{"date-parts":[[2015,3,31]],"date-time":"2015-03-31T01:06:02Z","timestamp":1427763962000},"page":"1413-1422","source":"Crossref","is-referenced-by-count":22,"title":["Partial depletion of striatal dopamine enhances penetrance of cognitive deficits in a transgenic mouse model of <scp>A<\/scp>lzheimer's disease"],"prefix":"10.1002","volume":"93","author":[{"given":"Erica J.","family":"Melief","sequence":"first","affiliation":[{"name":"Department of Pathology University of Washington Seattle Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eiron","family":"Cudaback","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Washington Seattle Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolas L.","family":"Jorstad","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Washington Seattle Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Sherfield","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Washington Seattle Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Postupna","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Washington Seattle Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Wilson","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Washington Seattle Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Darvas","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Washington Seattle Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen S.","family":"Montine","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Washington Seattle Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. 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